PFOS promotes Alzheimer's disease through aggravating the cell apoptosis and AKT/GSK3β/NF-κB/NLRP3 pathway mediated inflammation

Abstract

Perfluorooctane sulfonate (PFOS) and its alternatives are widely utilized in industrial and commercial applications. Nevertheless, their environmental persistence and widespread detection in diverse matrices in recent years have raised significant public health concerns. Studies reported that exposure to PFOS in cerebrospinal fluid will increase the risk of cognitive decline in humans. However, the underlying toxicological mechanism is still unclear. The aim of this study was to elucidate the possible toxic targets and potential molecular mechanisms of Alzheimer's disease (AD) induced by PFOS exposure through network toxicology, molecular docking and in vitro verification. Firstly, the results of network toxicology suggested that the mechanisms of PFOS-induced AD were mainly associated with the PI3K-AKT, neurodegeneration, apoptosis and NOD-like receptor signaling pathways. Subsequently, molecular docking simulations confirmed a strong binding interaction between PFOS and the key targets including SRC, ESR1, CASP3, BCL2, ERBB2, and TNF. Finally, we used HT22 and SH-SY5Y cell lines to validate the toxic effects of PFOS and found that PFOS aggravated neuronal cell apoptosis and AKT/GSK3β/NF-κB/NLRP3 pathway mediated inflammatory damages. Briefly, these findings indicated that PFOS exposure could affect the proliferation of neural cells by activating apoptosis and inflammatory related signaling pathways, thus promoting the occurrence and development of AD. This study provides a theoretical basis for understanding the molecular mechanisms involved in PFOS-induced neurotoxicity.